ABSTRACT The use of transgenic and gene knock-out genetically engineered animals is a powerful and informative approach that has been successfully undertaken by Core B in previous cycles to study neurodegenerative diseases. Core B provides Projects 1-4 with appropriately genotyped and aged mouse models of risk-factors for endosomal-lysosomal and autophagic abnormalities observed in Alzheimer's disease (AD) and Down syndrome (DS). A particular focus is the breeding of mouse models that reproduce a broad range of pathobiological phenotypes relevant to late-onset AD, especially related to the lysosomal network. Core B also serves to acquire novel animal models with these pathologies, and to generate novel crosses between these models and transgenic, knockin, or knockout models that carry or lack genes expected to affect AD-related pathologies. The models either express or are deficient of factors that are mechanistically linked to endosomal- lysosomal and autophagy pathology in all forms of AD, including the accumulation of the ?-site cleaved carboxyl-terminal fragment of the amyloid ? precursor protein (?CTF), such as in a mouse model of DS; the apolipoprotein E (ApoE) ?4 allele, the strongest genetic risk factor for late-onset AD; hyperactivation of rab5, the key mediator of endosome dysfunction in AD; and altered cholesterol levels, studied by high fat and cholesterol diet. Models of lysosomal abnormalities in AD will include loss-of-function of the presenilin 1 or 2 (PS1 and PS2) gene as well as high cholesterol diet. This Program Project focuses on the sources and mechanisms that lead to endosomal pathology (Project 1 and 4), lysosome and autophagy dysfunction (Projects 2 and 4), and exocytosis (Project 3), using multiple mouse models, many of which are shared by more than one project. The Core Leader has extensive experience managing a large mouse colony with complex breeding schemes, and will be able to coordinate animal breeding, genotyping, and delivery to Projects 1-4.